PROJECT SUMMARY/ABSTRACT A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex plays a key role in the pathophysiology of neuropsychiatric diseases such as depression, anxiety disorders, and addiction. These structural changes, such as the retraction of neurites and loss of dendritic spines, can potentially be counteracted by compounds capable of facilitating structural and functional neural plasticity. In fact, the promotion of neural plasticity in the prefrontal cortex has been proposed to play a crucial role in the therapeutic mechanism of fast-acting antidepressants and anxiolytics such as ketamine. Compounds from the iboga and ergoline families of natural products have shown enormous potential for promoting neuritogenesis, spinogenesis, and synaptogenesis in cortical neurons, and have demonstrated plasticity-promoting properties superior to ketamine. However, it is currently unknown which structural features of these molecules contribute to their efficacy. Our overall objective is to produce more effective and safer plasticity-promoting molecules through structure-activity relationship studies of these key scaffolds. To gain access to the large number of structural variants required for these studies, we propose novel synthetic routes to both the iboga and ergoline classes of natural products. The strategies we advance are significantly shorter than previously reported syntheses and allow for facile diversification and analog generation. The compounds that we design and synthesize will be assessed using novel in vitro neural plasticity assays developed in our lab. Ultimately, the work described here will fill the gap in our knowledge about how molecular structure impacts neural plasticity and will prove instrumental to the evolution of next-generation neurotherapeutics.